3d24

File:3d24.jpg

Crystal structure of ligand-binding domain of estrogen-related receptor alpha (ERRalpha) in complex with the peroxisome proliferators-activated receptor coactivator-1alpha box3 peptide (PGC-1alpha)

OverviewOverview

While structural studies on the ligand-binding domain (LBD) have established the general mode of nuclear receptor (NR)-coactivator interaction, determinants of binding specificity are only partially understood. The LBD of estrogen receptor (ER) alpha, for example, interacts only with a region of peroxisome proliferator-activated receptor coactivator (PGC)-1alpha that contains the canonical LXXLL motif (NR box2), whereas the LBD of estrogen-related receptor (ERR)alpha binds also efficiently an untypical, LXXYL-containing region (NR box3) of PGC-1alpha. Surprisingly, in a previous structural study, the ERalpha LBD has been observed to bind NR box3 of transcriptional intermediary factor (TIF)-2 untypically via LXXYL, while the ERRalpha LBD binds this region of TIF-2 only poorly. Here we present a new crystal structure of the ERRalpha LBD in complex with a PGC-1alpha box3 peptide. In this structure, residues N-terminal of the PGC-1alpha LXXYL motif form contacts with helix 4, the loop connecting helices 8 and 9, and with the C-terminus of the ERRalpha LBD. Interaction studies using wild-type and mutant PGC-1alpha and ERRalpha show that these contacts are functionally relevant and required for efficient ERRalpha/PGC-1alpha interaction. Furthermore, a structure comparison between ERRalpha and ERalpha and mutation analyses provide evidence that the helix 8-9 loop, which differs significantly in both nuclear receptors, is a major determinant of coactivator binding specificity. Finally, our results reveal that in ERRalpha the helix 8-9 loop allosterically links the LBD homodimer interface with the coactivator cleft, thus providing a plausible explanation for distinct PGC-1alpha binding to ERRalpha monomers and homodimers.

About this StructureAbout this Structure

3D24 is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.

ReferenceReference

Communication between the ERR alpha homodimer interface and the PGC-1alpha binding surface vie the helix 8-9 loop., Greschik H, Althage M, Flaig R, Sato Y, Peluso-Iltis C, Chavant V, Choulier L, Cronet P, Rochel N, Schule R, Stromstedt PE, Moras D, J Biol Chem. 2008 Apr 25;. PMID:18441008 Page seeded by OCA on Wed Jun 11 10:50:58 2008